Compounds for the treatment of hepatitis C

Abstract

The disclosure provides compounds of formula I, II, III, IV, and V, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

1. A compound of formula I or II 
       
         
           
           
               
               
           
         
       
       where:
 R 1  is phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR 7 R 8 , and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents; 
 R 2  is hydrogen, halo, alkyl, cycloalkyl, alkoxy, or R 5 R 6 N; 
 R 3  is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR 11 R 12 , (R 13 )(R 14 )NCONH, triazolyl, thiazolyl, or tetrazolyl; 
 R 4  is phenyl substituted with 0-2 halo; 
 R 5  is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, benzyl, alkylcarbonyl, haloalkylcarbonyl, phenylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, phenylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl; 
 R 6  is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; 
 or R 5  and R 6  taken together with the nitrogen to which they are attached is oxazolidinonyl or dioxothiazinyl; 
 R 7  is hydrogen, alkyl, 
 
       
         
           
           
               
               
           
         
         R 8  is hydrogen or alkyl; 
         R 9  is hydrogen or alkyl; 
         R 10  is hydrogen or alkyl; 
         or R 9  and R 10  taken together is ethylene, propylene, butylene, or pentylene; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen or alkyl; 
         or R 11  and R 12  taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 13  is hydrogen or alkyl; 
         R 14  is hydrogen or alkyl; 
         or R 13  and R 14  taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 15  is alkyl or cycloalkyl; 
         R 16  is hydrogen, halo, alkyl, or alkoxy; 
         R 17  is hydrogen, halo, alkyl, or alkoxy; and 
         Ar 1  is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo, alkyl, or phenyl substituents; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound of  claim 1  where
 R 1  is phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR 7 R 8 , and where said phenyl is substituted with 0-1 alkyl substituents; 
 R 2  is hydrogen, halo, alkoxy, or R 5 R 6 N; 
 R 3  is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR 11 R 12 , (R 13 )(R 14 )NCONH, triazolyl, thiazolyl, or tetrazolyl; 
 R 4  is phenyl substituted with 0-2 halo; 
 R 5  is alkylsulfonyl; 
 R 6  is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; 
 R 7  is hydrogen, alkyl, or 
 
       
         
           
           
               
               
           
         
         R 8  is hydrogen or alkyl; 
         R 9  is hydrogen or alkyl; 
         R 10  is hydrogen or alkyl; 
         or R 9  and R 10  taken together is ethylene, propylene, butylene, or pentylene; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen or alkyl; 
         R 13  is hydrogen or alkyl; 
         R 14  is hydrogen or alkyl; 
         or R 13  and R 14  taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 16  is hydrogen; 
         R 17  is hydrogen; and 
         Ar 1  is phenyl or pyridinyl; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. A compound of  claim 1  where
 R 1  is phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, and CONR 7 R 3 , and where said phenyl is also substituted with 0-2 alkyl substituents; 
 R 2  is hydrogen, halo or R 5 R 6 N; 
 R 3  is CONR 13 R 14 ; 
 R 4  is phenyl substituted with 0-2 halo; 
 R 5  is alkylsulfonyl; 
 R 6  is hydrogen or hydroxyalkyl; 
 R 7  is hydrogen, alkyl, or 
 
       
         
           
           
               
               
           
         
         R 8  is hydrogen; 
         R 9  is alkyl; 
         R 10  is alkyl; 
         or R 9  and R 10  taken together is ethylene or propylene; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen or alkyl; 
         R 13  is hydrogen or alkyl; 
         R 14  is hydrogen or alkyl; 
         or R 13  and R 14  taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 16  is hydrogen; 
         R 17  is hydrogen; and 
         Ar 1  is pyridinyl or phenyl, and is substituted with 0-1 alkyl or phenyl substituents; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound of  claim 1  where
 R 1  is phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, carboxy, and CONR 7 R 8 , and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents; 
 R 2  is hydrogen, halo, cycloalkyl, or R 5 R 6 N; 
 R 3  is CONR 11 R 12 ; 
 R 4  is phenyl substituted with 0-2 halo; 
 R 5  is hydrogen, (cycloalkyl)alkyl, benzyl, haloalkylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl; 
 R 6  is hydrogen or hydroxyalkyl; 
 R 7  is hydrogen, alkyl, 
 
       
         
           
           
               
               
           
         
         R 8  is hydrogen; 
         R 9  is alkyl; 
         R 10  is alkyl; 
         or R 9  and R 10  taken together is ethylene or propylene; 
         R 11  is alkyl; 
         R 12  is hydrogen; 
         R 15  is alkyl or cycloalkyl; 
         R 16  is hydrogen; 
         R 17  is hydrogen; and 
         Ar 1  is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 alkyl or phenyl substituents; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. A compound of  claim 1  where R 1  is phenyl substituted with 1 CONR 7 R 8  substituent and 0-2 halo, alkyl, or alkoxy substituents; R 2  is hydrogen, halo, alkyl, or R 5 R 6 N; R 3  is CONR 11 R 12 ; R 4  is monofluorophenyl; R 5  is alkylsulfonyl; R 6  is alkyl; R 7  is 
       
         
           
           
               
               
           
         
       
       R 8  is hydrogen; R 9  is methyl; R 10  is methyl; or R 9  and R 10  taken together is ethylene; R 11  is alkyl; R 12  is hydrogen or alkyl; R 16  is hydrogen; R 17  is hydrogen; and Ar 1  is oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo or alkyl substituents; or a pharmaceutically acceptable salt thereof. 
     
     
       6. A compound of  claim 1  where R 1  is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR 7 R 8 , and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents. 
     
     
       7. A compound of  claim 1  where R 1  is phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR 7 R 8 , and where said phenyl is substituted with 0-1 halo, alkyl, or alkoxy substituents. 
     
     
       8. A compound of  claim 1  selected from the group consisting of
 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide; 
 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide; 
 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 
 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 
 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 
 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 
 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)phenyl)-N-methylpyrazolo[1,5-c]pyridine-3-carboxamide; 
 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide; and 
 4-fluoro-2-(4-fluorophenyl)-5-(5-(1-(3-fluorophenyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       9. A composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       10. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient.